A prominent characteristic of Alzheimer's disease is the loss of brain nerve cells that employ the neurotransmitter acetylcholine. Cholinergic neurons may be lost as a consequence of the formation of toxic deposits, known as neuritic plaques, which contain beta amyloid peptides as a major component. However, the correlation between amyloid deposition and cognitive impairment appears to be poor. On the other hand, target receptors for acetylcholine may be affected, indicating an action of soluble beta amyloid. Indeed, beta amyloid has recently been shown to interact directly with nicotinic receptors on neuronal cell bodies. In brain, a substantial portion of the nicotinic receptors are localized to presynaptic nerve endings. Preliminarily, it was found that beta amyloid first activates and then occludes presynaptic nicotinic receptor-induced functional responses in isolated hippocampal nerve endings, but does not affect responses mediated by the closely related 5-HT3 serotonin receptors co-localized with the nicotinic receptors on the same nerve endings. Thus, it is hypothesized that soluble beta amyloid selectively alters neuronal signaling via disruption of postsynaptic and presynaptic nicotinic receptors in the brain. The specific aims of this proposal are to characterize the effects of beta amyloid peptides on 1) nicotine-induced calcium responses and neurosecretion in individual nerve endings using confocal microscopy; 2) neurotransmitter release in vivo using microdialysis; and 3) initiation of nerve terminal degenerative responses to prolonged beta amyloid treatment, including mitochondria depolarization and calcium dysregulation, and the possible role of protein phosphorylation in these events. In each case, mouse hippocampus, cortex, and, on a limited basis as a control, striatum will be examined. The use of inbred mice will allow studies with transgenic mouse models, including the APP mutant APPswe/PS1 and nicotinic receptor null mutants, allowing definite determination of which particular presynaptic nicotinic receptor subunits are targets for beta amyloid and what effect chronic beta amyloid has on presynaptic nicotinic receptor function. Nicotinic receptors have been strongly implicated in memory mechanisms in the brain. Their disruption by elevated soluble beta amyloid may cause alterations in neuronal signaling in early Alzheimer's disease leading to reduced cognitive function. The role of presynaptic nicotinic receptors may be key, as these receptors are prominently localized to nerve endings in the brain. Characterizing the functional effects of beta amyloid on presynaptic nicotinic receptors may thus yield important information related to early events in Alzheimer's disease.